Ikegami H et al.:Immune checkpoint therapy and type 1 diabetes. Diabetol Int 7，221-227，2016.
Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB.
Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition.
Diabetes Care. 2015 Sep;38(9):1687-93. doi: 10.2337/dc15-0843. Epub 2015 Jun 15.
Abstract/Text
OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication.
RESEARCH DESIGN AND METHODS: Cases identified incidentally are described.
RESULTS: We identified 13 episodes of SGLT-2 inhibitor-associated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers.
CONCLUSIONS: SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
David E Trachtenbarg
Diabetic ketoacidosis.
Am Fam Physician. 2005 May 1;71(9):1705-14.
Abstract/Text
A diagnosis of diabetic ketoacidosis requires the patient's plasma glucose concentration to be above 250 mg per dL (although it usually is much higher), the pH level to be less than 7.30, and the bicarbonate level to be 18 mEq per L or less. Beta-hydroxybutyrate is a better measurement of the degree of ketosis than serum ketones. Intravenous insulin and fluid replacement are the mainstays of therapy, with careful monitoring of potassium levels. Phosphorous and magnesium also may need to be replaced. Bicarbonate therapy rarely is needed. Infection, insulin omission, and other problems that may have precipitated ketoacidosis should be treated. Myocardial infarction is a precipitating cause of diabetic ketoacidosis that is especially important to look for in older patients with diabetes. Cerebral edema is a major complication that occurs primarily in children. Education to prevent recurrence should be offered to all patients, including how to manage sick days and when to call a physician.
Abbas E Kitabchi, Guillermo E Umpierrez, John M Miles, Joseph N Fisher
Hyperglycemic crises in adult patients with diabetes.
Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032.
Abstract/Text
A E Kitabchi, G E Umpierrez, M B Murphy, E J Barrett, R A Kreisberg, J I Malone, B M Wall
Management of hyperglycemic crises in patients with diabetes.
Diabetes Care. 2001 Jan;24(1):131-53.
Abstract/Text
Gregg D Stoner
Hyperosmolar hyperglycemic state.
Am Fam Physician. 2005 May 1;71(9):1723-30.
Abstract/Text
Hyperosmolar hyperglycemic state is a life-threatening emergency manifested by marked elevation of blood glucose, hyperosmolarity, and little or no ketosis. With the dramatic increase in the prevalence of type 2 diabetes and the aging population, this condition may be encountered more frequently by family physicians in the future. Although the precipitating causes are numerous, underlying infections are the most common. Other causes include certain medications, non-compliance, undiagnosed diabetes, substance abuse, and coexisting disease. Physical findings of hyperosmolar hyperglycemic state include those associated with profound dehydration and various neurologic symptoms such as coma. The first step of treatment involves careful monitoring of the patient and laboratory values. Vigorous correction of dehydration with the use of normal saline is critical, requiring an average of 9 L in 48 hours. After urine output has been established, potassium replacement should begin. Once fluid replacement has been initiated, insulin should be given as an initial bolus of 0.15 U per kg intravenously, followed by a drip of 0.1 U per kg per hour until the blood glucose level falls to between 250 and 300 mg per dL. Identification and treatment of the underlying and precipitating causes are necessary. It is important to monitor the patient for complications such as vascular occlusions (e.g., mesenteric artery occlusion, myocardial infarction, low-flow syndrome, and disseminated intravascular coagulopathy) and rhabdomyolysis. Finally, physicians should focus on preventing future episodes using patient education and instruction in self-monitoring.
M I Wiggam, M J O'Kane, R Harper, A B Atkinson, D R Hadden, E R Trimble, P M Bell
Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study.
Diabetes Care. 1997 Sep;20(9):1347-52.
Abstract/Text
OBJECTIVE: To compare the efficacy of an extended insulin regimen using correction of hyperketonemia as endpoint with a more conventional regimen in the treatment of diabetic ketoacidosis.
RESEARCH DESIGN AND METHODS: A total of 22 patients admitted to a Belfast teaching hospital with clinical and biochemical features of diabetic ketoacidosis (pH < 7.25 and/or bicarbonate < 16 mmol/l) were randomized to either conventional or extended insulin regimens. In the conventional regimen, insulin was administered at 5 U/h until near-normoglycemia (blood glucose < or = 10 mmol/l) and then administered at a reduced rate until clinical recovery. In the extended regimen, administration of insulin at 5 U/h was continued beyond attainment of normoglycemia, until resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/l). Main outcome measures were 3-hydroxybutyrate and bicarbonate levels during the 24 h after attainment of near-normoglycemia.
RESULTS: After near-normoglycemia, correction of hyperketonemia was achieved earlier with the extended treatment (5.9 +/- 0.8 vs. 21.8 +/- 3.4 h, P = 0.0004 [mean +/- SD]). The area under the curve of 3-hydroxybutyrate against time for 24 h after near-normoglycemia was reduced with the extended treatment (24.9 +/- 3.8 vs. 55.9 +/- 6.7 mmol.l-1.h-1, P = 0.001). These differences remained statistically significant after adjustment for higher baseline levels of 3-hydroxybutyrate at near-normoglycemia in the extended treatment group. Bicarbonate levels at 6 and 12 h after near-normoglycemia were not significantly different between groups.
CONCLUSIONS: The extended insulin regimen, which was easy to implement at ward level, produced a more rapid resolution of ketosis than the conventional regimen.
G Gamba, J Oseguera, M Castrejón, F J Gómez-Pérez
Bicarbonate therapy in severe diabetic ketoacidosis. A double blind, randomized, placebo controlled trial.
Rev Invest Clin. 1991 Jul-Sep;43(3):234-8.
Abstract/Text
Intravenous sodium bicarbonate has been used for a long time in the treatment of diabetic ketoacidosis. However, there are no clinical studies showing its effectiveness in improving arterial pH in this condition. We therefore designed this study to investigate if bicarbonate therapy improves the rate of increase of arterial pH and to find out its effects on the recovery rate of the other metabolic abnormalities. Twenty patients with severe diabetic ketoacidosis (pH less than 7.15) entered a double-blind, randomized, placebo controlled trial: nine were included in the bicarbonate group and eleven in the placebo group. All patients were studied during the first 24 hours of treatment. Their management was similar, except for the use of sodium bicarbonate in one group and 0.9% saline solution in the placebo group. Heart rate, respiratory rate, arterial pressure, mental status, blood gases, blood glucose, sodium, potassium, and urea were assessed at the beginning of treatment, and then at 2, 6, 12 and 24 hours. No clinical or metabolic differences were found between groups. Two hours after therapy was begun, the arterial pH rose in the bicarbonate group from 7.05 +/- 0.08 to 7.24 +/- 0.04, while it only rose from 7.04 +/- 0.08 to 7.11 +/- 0.09 in the placebo group (p less than 0.02). Simultaneously, arterial bicarbonate increased from 2.87 +/- 1.2 to 6.1 +/- 1.5 mEq/L in the bicarbonate group and from 2.55 +/- 0.81 to 3.6 +/- 2 mEq/L in the placebo group (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
L R Morris, M B Murphy, A E Kitabchi
Bicarbonate therapy in severe diabetic ketoacidosis.
Ann Intern Med. 1986 Dec;105(6):836-40.
Abstract/Text
Twenty-one adult patients with severe diabetic ketoacidosis entered a randomized prospective protocol in which variable doses of sodium bicarbonate, based on initial arterial pH (6.9 to 7.14), were administered to 10 patients (treatment group) and were withheld from 11 patients (control group). During treatment, there were no significant differences in the rate of decline of glucose or ketone levels or in the rate of increase in pH or bicarbonate levels in the blood or cerebrospinal fluid in either group. Similarly, there were no significant differences in the time required for the plasma glucose level to reach 250 mg/dL, blood pH to reach 7.3, or bicarbonate level to reach 15 meq/L. We conclude that in severe diabetic ketoacidosis (arterial pH 6.9 to 7.14), the administration of bicarbonate does not affect recovery outcome variables as compared with those in a control group.
Abbas E Kitabchi, Mary Beth Murphy, Judy Spencer, Robert Matteri, Jim Karas
Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis?
Diabetes Care. 2008 Nov;31(11):2081-5. doi: 10.2337/dc08-0509. Epub 2008 Aug 11.
Abstract/Text
OBJECTIVE: The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose.
RESEARCH DESIGN AND METHODS: This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit x kg(-1) x h(-1) i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit . kg body weight(-1) x h(-1) without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 x kg(-1) x h(-1) without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA.
RESULTS: The load group reached a peak in free insulin value (460 microU/ml) within 5 min and plateaued at 88 microU/ml in 60 min. The twice no load group reached a peak (200 microU/ml) at 45 min. The no load group reached a peak (60 microU/ml) in 60-120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose or=7.3, and HCO(3)(-) >or=15 mEq/l did not differ significantly among the three groups.
CONCLUSIONS: A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit x kg body weight(-1) x h(-1) (about 10 units/h in a 70-kg patient) is given.
Maryann Mazer, Esther Chen
Is subcutaneous administration of rapid-acting insulin as effective as intravenous insulin for treating diabetic ketoacidosis?
Ann Emerg Med. 2009 Feb;53(2):259-63.
Abstract/Text
To determine whether intermittent subcutaneous administration of rapid-acting insulin is as effective as intravenous infusion of regular insulin for treating uncomplicated diabetic ketoacidosis, we performed a MEDLINE, EMBASE, and Cochrane Library search, using the key words "subcutaneous insulin AND intravenous insulin AND diabetic ketoacidosis; LIMIT humans and English." We also searched the references in these articles for additional studies. This search yielded a total of 35 articles, 4 of which directly addressed the question at hand. According to this review of the available evidence; subcutaneous administration of rapid-acting insulin analogs such as lispro is as effective and safe as intravenous infusion of regular insulin for the management of uncomplicated diabetic ketoacidosis. In addition, use of insulin analogs may confer an overall cost savings, obviating the need for infusion pumps and ICU admissions in certain institutions. Therefore, it would be safe and effective to use subcutaneously administered rapid-acting insulin analogues instead of intravenous regular insulin infusions for patients with uncomplicated diabetic ketoacidosis.
Guillermo E Umpierrez, Sidney Jones, Dawn Smiley, Patrick Mulligan, Trevor Keyler, Angel Temponi, Crispin Semakula, Denise Umpierrez, Limin Peng, Miguel Cerón, Gonzalo Robalino
Insulin analogs versus human insulin in the treatment of patients with diabetic ketoacidosis: a randomized controlled trial.
Diabetes Care. 2009 Jul;32(7):1164-9. doi: 10.2337/dc09-0169. Epub 2009 Apr 14.
Abstract/Text
OBJECTIVE: To compare the safety and efficacy of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with diabetic ketoacidosis (DKA).
RESEARCH DESIGN AND METHODS: In a controlled multicenter and open-label trial, we randomly assigned patients with DKA to receive intravenous treatment with regular or glulisine insulin until resolution of DKA. After resolution of ketoacidosis, patients treated with intravenous regular insulin were transitioned to subcutaneous NPH and regular insulin twice daily (n = 34). Patients treated with intravenous glulisine insulin were transitioned to subcutaneous glargine once daily and glulisine before meals (n = 34).
RESULTS: There were no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA between intravenous treatment with regular and glulisine insulin. After transition to subcutaneous insulin, there were no differences in mean daily blood glucose levels, but patients treated with NPH and regular insulin had a higher rate of hypoglycemia (blood glucose <70 mg/dl). Fourteen patients (41%) treated with NPH and regular insulin had 26 episodes of hypoglycemia and 5 patients (15%) in the glargine and glulisine group had 8 episodes of hypoglycemia (P = 0.03).
CONCLUSIONS: Regular and glulisine insulin are equally effective during the acute treatment of DKA. A transition to subcutaneous glargine and glulisine after resolution of DKA resulted in similar glycemic control but in a lower rate of hypoglycemia than with NPH and regular insulin. Thus, a basal bolus regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA.
J N Fisher, A E Kitabchi
A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis.
J Clin Endocrinol Metab. 1983 Jul;57(1):177-80. doi: 10.1210/jcem-57-1-177.
Abstract/Text
The use of phosphate therapy in the management of diabetic ketoacidosis (DKA) has been controversial, particularly with respect to the effect of phosphate intermediates on tissue oxygenation. In a prospective randomized study we evaluated the effect of phosphate (8.5 mmol/h or approximately 6 g phosphate/24 h) (experimental group) vs. no phosphate therapy (control group) in 30 DKA patients, 15 in each group. Various determinations including erythrocyte 2,3-diphosphoglycerate (2,3-DPG), oxyhemoglobin dissociation (p50), serum phosphate, calcium, lactate, pyruvate, electrolytes, and response time to reach predetermined values for glucose, bicarbonate, and pH were measured at frequent intervals during the first 24 h of therapy and daily for 5 days after metabolic control. Initial electrolytes, glucose, pH, erythrocyte 2,3-DPG, lactate, and p50 were not different in either group. Whereas the experimental group had a greater level of 2,3-DPG than the control group by 48 h, the difference was not statistically significant. Recovery indices, including hours to reach glucose of 250 mg/dl, bicarbonate greater than 15 meq/liter, pH greater than 7.3, and mental alertness, were not different in the two groups nor were the p50 or lactate measurements. The experimental group exhibited significantly lower plasma ionized calcium values during therapy. We conclude that phosphate therapy may accelerate regeneration of erythrocyte 2,3-DPG but in the relatively small number of patients studied it had no demonstrable influence on tissue oxygenation or clinical response to low dose insulin therapy of DKA. Furthermore, the exaggeration of hypocalcemia seen in phosphate-treated patients may be reason for caution in the use of such therapy.
